The incidence of surgical site infection following major lower limb amputation: A systematic review

Abstract Surgical site infections (SSIs) following major lower limb amputation (MLLA) in vascular patients are a major source of morbidity. The objective of this systematic review was to determine the incidence of SSI following MLLA in vascular patients. This review was prospectively registered with the International Prospective Register of Systematic Reviews (CRD42023460645). Databases were searched without date restriction using a pre‐defined search strategy. The search identified 1427 articles. Four RCTs and 21 observational studies, reporting on 50 370 MLLAs, were included. Overall SSI incidence per MLLA incision was 7.2% (3628/50370). The incidence of SSI in patients undergoing through‐knee amputation (12.9%) and below‐knee amputation (7.5%) was higher than the incidence of SSI in patients undergoing above‐knee amputation, (3.9%), p < 0.001. The incidence of SSI in studies focusing on patients with peripheral arterial disease (PAD), diabetes or including patients with both was 8.9%, 6.8% and 7.2%, respectively. SSI is a common complication following MLLA in vascular patients. There is a higher incidence of SSI associated with more distal amputation levels. The reported SSI incidence is similar between patients with underlying PAD and diabetes. Further studies are needed to understand the exact incidence of SSI in vascular patients and the factors which influence this.


Key Messages
• Surgical site infection (SSI) is a frequent complication following major lower limb amputation (MLLA) in patients with peripheral arterial disease.• Incidence of post-operative SSI varies based on the level of MLLA, with through-knee and below-knee amputations showing higher SSI rates than above-knee amputations.• Heterogeneity exists in the current reporting of SSI post-MLLA in the literature.• Future research should prioritise investigating interventions influencing SSI incidence and establishing a standardised reporting system for SSI in this patient population.

| INTRODUCTION
Major lower limb amputation (MLLA) is commonly performed in patients with ischaemia, severe infection or following major trauma. 1 Most people who undergo MLLA have peripheral arterial disease (PAD), diabetes or both, 2,3 as well as other risk factors for the development of surgical site infection (SSI) such as tobacco use. 4 SSIs are associated with increased patient morbidity and mortality. 5The Centres for Disease Control and prevention (CDC) classifies SSIs into incisional, which are superficial or deep, and organ/space SSIs. 6Developing an SSI post-MLLA can lead to prolonged hospital admission, additional medical therapy such as prolonged courses of antibiotics, and in more serious cases, surgical drainage, and revision of the amputation stump, including amputation to a higher level. 7The National Confidential Enquiry into Patient Outcome and Death (NCEPOD) document 'Major Lower Limb Amputation: Working Together' published in 2013 reported that MLLA stump complications were not infrequent, with cellulitis occurring in 16.4% and breakdown in 20.4%, 8 whether this was secondary to infection, ischaemia or a combination of the two was not reported.
Post-operative wound infection was identified as a core outcome for vascular patients undergoing MLLA in 2020 by focus groups including patients and healthcare professionals. 9The James Lind Alliance research priority setting partnership also identified improving clinical outcomes and healing of the amputation stump (residual limb) as two of the top priorities in vascular patients undergoing MLLA in 2021. 10Understanding the incidence of SSI in this population is therefore paramount.Currently, the incidence of SSI in patients who have undergone a MLLA for vascular disease is not well documented.The primary objective of this systematic review is to identify the reported incidence of SSI post-MLLA for patients with underlying PAD or diabetes overall and within 30 days of surgery.Secondary objectives were to determine the incidence of SSI by aetiology (PAD or diabetes), exact amputation level and study type (randomised controlled trial (RCT) vs. observational study).

| MATERIALS AND METHODS
The protocol for this study outlining the objectives of the review, methods of data collection and analysis was prospectively registered with the International Prospective Register of systematic reviews (PROSPERO; CRD42023460645).This systematic review is reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement. 11

| Inclusion and exclusion criteria and data sources
RCTs, observational cohort studies and case series with >10 cases which met the inclusion criteria below were included in this review.Editorials, conference abstracts, reviews and case reports were excluded.There was no restriction on publication date.
Inclusion criteria: 1. Patients >18 years old 2. Studies including patients undergoing MLLA (aboveknee amputation (AKA), below-knee amputation (BKA), through-knee amputation (TKA) or equivalent) Studies identified in the searches were exported onto Microsoft Excel.All duplicate articles were removed before screening.Each study was screened according to title and abstract by two reviewers (NAS and KAH), with conflicts resolved by a third reviewer (MLW).Full-text screening was conducted by two reviewers (NAS and KAH); again, conflicts were resolved by a third reviewer (MLW).For the studies where the incidence of SSI following MLLA related to diabetes and/or PAD could not be extracted (n = 7), the authors were contacted and a request for the data was made.
The primary outcome was the reported incidence of SSI post-MLLA overall and within 30 days.Secondary outcomes were the incidence of SSI based on: 1.The specific level of major amputation reported in the studies (above-knee amputation (AKA), below-knee amputation (BKA) or through-knee amputation (TKA)) 2. Study design (RCT/observational) 3. Study arms (intervention/control) 4. Underlying pathology (peripheral arterial disease and/or diabetes) 5. Reported definition used to diagnose SSI (CDC/ASEP-SIS/author-defined) 6.Whether SSI was a primary outcome (including a coprimary outcome or component of a composite outcome) Data were organised and extracted by two reviewers independently (NAS and KAH), and discrepancies were checked by a third reviewer who was the senior author (MLW).The data collection tool was piloted and refined to ensure the capture of all relevant data.Study risk of bias assessment was undertaken by two reviewers (NAS and KAH).Cochrane's risk of bias tool 12 was used for RCTs, and the Newcastle-Ottawa scale 13 was used for observational studies.All studies were included in the analysis.The SSI incidence has been reported per MLLA for all patients who met the inclusion criteria.For RCTs, the incidence of SSI in both the intervention and control groups was included.

| Synthesis methods
The data collection methodology was specifically designed to facilitate the calculation of the actual incidence of SSI per MLLA incision.This was carried out for the studies overall and for the subgroups.Demographic variables, including the percentage of male patients and mean age, were aggregated, where possible, using the weighted mean.Categorical data were compared using the Chi-squared test.Analyses were performed using Excel (Microsoft) and Prism 10 software version 10.1.0,GraphPad Software LLC.

| RESULTS
The initial search performed on 13 February produced 1427 results.After the removal of duplicates, 1240 studies were screened and assessed for eligibility.Following the title and abstract screening, 57 articles underwent fulltext review.After further exclusions, 25 studies were retained for data extraction (Figure 1).Table 1 reports the study demographics.

| Demographic details
The included studies were published between 1982 and 2023.Studies included were RCTs (n = 4) and observational (n = 21).Overall, across the studies, there were 50 370 MLLAs related to underlying PAD and/or diabetes undertaken in 50 263 patients.The weighted mean age was 70.5 years.The mean percentage of male patients in the studies was 67.6%.
Studies were grouped according to the underlying pathology described in the study's patient cohort: diabetes (n = 2), PAD (n = 14) or both (diabetes and PAD) (n = 9).Studies were also grouped according to the level of major amputation in the study cohort: AKA only (n = 1), BKA only (n = 4), TKA only (n = 4) or AKA ± BKA ± TKA (n = 19).When all the studies were pooled, there were 25 015 AKAs, 25 032 BKAs and 323 TKAs across all the studies.SSI was a primary outcome in 19 studies.The incidence of SSI within 30 days was reported in 12 studies.
Definitions used to report SSI included the CDC criteria (n = 7), ASEPSIS score (n = 1) and author definition (n = 4).In the remaining studies (n = 13), it was not reported how SSI was defined.
The severity of SSI (superficial/deep) was reported in 6 studies.Of these studies, 3 used the CDC criteria, 2 did not report how SSI was defined and 1 used an author definition.Table 2 reports study demographics according to outcomes and SSI definition.

| Risk of bias in studies
The reviewers determined one of the RCTs had a high risk of bias, one had some concern for bias and two had a low risk of bias (Table 3).The median Newcastle-Ottawa score for observational studies was 6, and the range was 3 to 8 (Table 4).

| Overall SSI rates
There were 3628 SSIs in 50 370 MLLAs, which equates to an SSI incidence 7.2% per MLLA.This is the incidence of SSI across all the studies during their follow-up period (21-781 days).The weighted SSI incidence was also 7.2%.Figure 2 represents the incidence of SSI per MLLA in each study.
In studies which reported the degree of SSI, there were more superficial SSIs reported across the studies (1096/28792, 3.8%) compared with deep SSIs (646/28792, 2.2%).In studies which reported the incidence of SSI according to the level of amputation (n = 18), the SSI incidence in patients undergoing TKA and BKA was higher than the incidence of SSI in patients undergoing AKA (12.9%, 7.5% and 3.9%, respectively, p < 0.001).
In studies where SSI was a primary, coprimary or component of a composite primary outcome, the incidence of SSIs was 7.1% (3285/46378); in studies where SSI was a secondary outcome, the incidence of SSI was  8.5% (343/4013).In studies which used a formal definition to report SSI (n = 8), the incidence of SSI was 7.3% (2497/34332).Table 5 summarises the incidence of SSI according to the study type, outcomes and patient characteristics.
The year of publication for each study was used as a surrogate for the date of surgery.The incidence of SSI per MLLA decreased over time.Figure 3 shows the incidence of SSI per MLLA by year of study publication.

| Incidence of SSI within 30 days
Ten observational studies and 2 RCTs reported the incidence of SSI within 30 days.Overall, there were 2799 SSIs reported in 40 038 MLLAs within 30 days.This equates to an SSI incidence of 7.0%.The incidence of superficial and deep SSIs within 30 days was 3.8% (1092/28724) and 2.2% (637/28724), respectively.

| Randomised control trials
In RCTs, the incidence of SSIs during the study follow-up period was 18.8% (50/266).The incidence of superficial and/or deep SSIs was not reported by any of the RCTs.The control arms of the RCTs experienced a higher incidence of SSIs (16.2%; 43/266) than the intervention groups (2.6%; 7/266).
SSI was a primary outcome in all the RCTs.Of the four RCTs, the underlying pathology was diabetes in one study, PAD only in two of the studies and both in one study.The incidence of SSI was similar in the RCTs which included diabetes as the underlying pathology (24/136, 17.6%) compared with the studies that only included patients with PAD (26/130, 20%).
Skin preparation was evaluated in two of the studies (preparation vs. no preparation, and chlorhexidine vs. povidone-iodine), antibiotic therapy in one study (24 h vs. 5-day antibiotic prophylaxis), closed incision negative wound therapy (CiNPWT) versus standard dressing in one study and one-versus two-staged amputations for patients with diabetes-related amputations in one study.Two of the RCTs used a formal definition to report SSI (ASEPSIS score and the CDC criteria).

| Observational studies
In observational studies, the overall incidence of SSIs was 7.1% (3578/50104).In studies that included patients with both PAD and diabetes as the underlying pathology, the incidence of SSIs was 6.8% (1386/20243) in patients with ).Studies that had SSI as a primary outcome had a similar overall reported SSI incidence when compared with studies where SSI was not a primary outcome (7.1% and 8.5%, respectively).Six studies reported the severity of SSI, the incidence of superficial and deep SSI in these studies was 3.8% and 2.2%, respectively.

| Use of antibiotic prophylaxis
The use of prophylactic antibiotics was sporadic and inconsistent when reported.Sixteen studies did not record whether antibiotics were used or not.Four  reported the use of pre-operative antibiotics (before knife to skin) alone, 3 studies used pre-and post-operative antibiotics using various preparations and durations (1-15 days), one study reported that antibiotic use was surgeon dependent but was not recorded and another 44/63 patients received some form of antibiotic therapy, but the type and duration was not recorded.One of these studies investigated the impact of extended post-operative antibiotic prophylaxis and found significant SSI reduction in those that received them for 5 days. 31

| DISCUSSION
This systematic review has identified 25 studies with a combined SSI incidence of 7.2% and a 30-day SSI incidence of 7.0%, following MLLA performed related to diabetes or underlying PAD.This highlights the significance of this complication in this cohort of patients.The studies included in this review were published over 40 years.
Observational studies reported a lower overall incidence of SSI following MLLA when compared with RCTs.However, from the studies, only four were RCTs.These RCTs used protocol-driven follow-up methods, while the observational studies often relied on hospital or national database records which may inconsistently report patient outcomes. 395 Registries are often subject to inaccuracies and missing data which could explain the lower reported incidence of SSI. 40Furthermore, those with less severe SSI usually receive treatment in the primary care setting, and this information may also be missed in retrospective observational studies due to the nature of follow-up. 41A similar trend has been reported in a systematic review of groin wound SSI following vascular surgery. 42he incidence of SSI according to severity(superficial or deep) was reported in six of the studies. 15,16,19,21,23,33n these studies, there was a higher reported incidence of superficial SSIs.Deep SSIs are more likely to require intervention compared a superficial SSI. 43This could have a significant impact on a patient's quality of life, psychology, rehabilitation potential and ability to use a prosthesis. 34,44SSIs in patients following vascular surgery have also been identified to substantially increase the costs for healthcare systems. 45imilar incidences of SSI were reported in the studies grouped according to underlying disease (PAD and/or diabetes).Two studies assessed MLLAs in diabetic patients, yet there were differences in patient cohorts. 15,20ne study looked at all diabetic patients undergoing MLLA, 15 whilst the other concentrated on diabetic patients with wet gangrene, 20 which is likely to carry a different baseline risk for developing an SSI.Furthermore, the degree and pattern of ischaemia were not reported uniformly for all the patients, and this may have an impact on post-operative wound healing.Previous studies have highlighted that perfusion of the stump likely contributes to increased rates of stump breakdown F I G U R E 2 Graph illustrating the incidence of SSI (%) in each of the studies, including the intervention and control arms of the RCTs.
T A B L E 5 The incidence of SSI according to study design, patient cohort and group.and infection in all patients, often necessitating surgical revision, 7,46 and diabetes is known to be a risk factor for SSI.The precise contribution of both factors in this patient cohort warrants further investigation.A study with robust follow-up is essential to accurately determine the discrepancy in SSI rates following MLLA among patients undergoing amputation due to PAD, diabetesrelated complications or both.The lower incidence of SSIs in patients with aboveknee amputations (compared with BKA/TKA) has been reported consistently in previous studies and an NCE-POD report. 8,48,49The decision to have a more distal amputation is multifactorial.Surgeon and patient preference for a longer stump which is more functional may impact the decision to undergo a TKA or BKA compared with an AKA. 50Also, for individual vascular units in the UK, a BKA to AKA ratio of greater than 1 is a quality performance indicator. 51he control arms of the RCTs consistently reported higher incidence of SSI than the intervention arms.The RCTs each evaluated a different intervention, from CiNWPT, antibiotic prophylaxis and different skin preparations pre-operatively. 20,29,31,34All the RCTs reported SSIs as a primary outcome and were published from 1989 to 2023.Reviewers noted significant concerns when evaluating the risk of bias in two of the RCTs.One trial exhibited a high risk of bias due to deviations from the intended intervention 29 while another faced issues related to the selection of reported results. 20Despite concerns regarding some of the methodology in these studies, the incidence of SSI across all four RCTs remained similar.The scarcity of recent RCTs in this field highlights further studies are required to determine the best interventions to prevent SSI post-MLLA in this patient group.Vascular surgeons have demonstrated a willingness to randomise patients to interventions and reduce SSI. 52here was heterogeneity in the criteria used to identify SSIs across the studies.Notably, studies which used the CDC criteria and ASEPSIS score reported a higher incidence of SSI in comparison with studies that used an author-specified definition.Differences in SSI reporting due to the adoption of different definitions have been previously acknowledged. 42Also, it is important to note that several studies used data from the ACS-NSQIP database and whilst this is validated and utilises the CDC criteria, it is not without its limitations. 15ncluded studies were published over 35 years, during which significant changes occurred in surgical practices for both the prevention and management of SSIs.There was also heterogeneity in the criteria used to diagnose and report SSIs across the included studies.This variation in definitions and methodologies made it difficult to directly compare SSI incidence, affecting the overall reliability of our conclusions.Nearly half of the studies included were found to possess a high risk of bias and low quality.However, their inclusion was thought necessary due to the scarcity of literature on this topic and the incidence of SSI was similar in the RCTs, despite the methodological concerns.The factors which influence the incidence of SSIs were not reported in most of the reviewed studies.The lack of uniformity in presenting data on patient-specific factors, such as smoking or diabetic status, limited our ability to explore associations between these variables and the incidence of SSI.Our understanding of the intricate relationships between these factors and SSI incidence therefore remains limited and supports the adoption of a standardised reporting system.

| CONCLUSIONS
The combined incidence of SSI following MLLA undertaken secondary to underlying PAD or diabetes reported extracted from the literature was 7.2%.The incidence of SSI in patients undergoing TKA or BKA is higher than those undergoing AKA.There is heterogeneity in the reporting of SSIs in this patient cohort in the existing literature.The incidence of SSI in observational studies is lower than those reported in RCTs.Higher quality evidence is required to ascertain the true incidence of SSI in this population.
Brenig Llwyd Gwilym https://orcid.org/0000-0002-5403-8720David C. Bosanquet https://orcid.org/0000-0003-2304-0489 No English version of the full text is available 2.2 | Review process: Data collection process, data items, study risk of bias assessment The search strategy was developed and tested in collaboration with a clinical librarian.The MEDLINE, EMBASE and CENTRAL databases were searched on 13 February 2024 using the search terms [SSI OR SSIs OR surgical site infection OR surgical wound infection OR wound infection] AND [vascular OR arterial OR diabetes OR diabetic OR gangrene] AND [(amputation AND lower limb) OR MLLA OR MLEA OR above knee amputation OR AKA or below knee amputation OR BKA OR through knee amputation OR TKA OR transfemoral OR transtibial].
Study demographic data.
T A B L E 1 Study demographics based on SSI outcomes.
T A B L E 1 (Continued) Studies which used an existing SSI definition (n = 7) reported an SSI rate of 7.3% (2464/34171) and those which used an author definition reported an SSI rate of 5.2% (184/3523 47